Parkinson's disease is a brain disease characterized by tremor, bradykinesia, difficulty in gait and coordinated movement and the like. This disease is associated with damage of a part of brain which governs muscle movements. Generally, the first symptom of Parkinson's disease is a limb tremor (shaking or trembling) particularly when the body is at rest. Tremor often begins in the hemibody, and frequently occurs in one of the hands. Other common symptoms include slow movement (bradykinesia), an inability to move (akinesia), a rigidity of trunk and limbs, a shuffling gait, and a stooped posture and the like. Patients with Parkinson's disease are poor in facial expression, and tend to speak in a soft voice. Parkinson's disease can cause secondary symptoms such as depression, anxiety, personality change, cognitive impairment, dementia, sleep disturbances, speech impairments or sexual dysfunction. The drug therapy of Parkinson's disease currently employed clinically mainly controls the parkinsonian symptoms by controlling the imbalance among neurotransmitters. Early stage patients of Parkinson's disease mostly respond well to a symptomatic therapy by a dopamine replacement therapy; however, the disability increases with progression of the disease.
Although currently available medications for Parkinson's disease generally provide adequate symptomatic control for several years, however, many patients develop motor fluctuations and dyskinesias that compromise clinical response (The New England Journal of Medicine (N. Eng. J. Med.), vol. 342, p. 1484 (2000) and the like).
Although more than thirty years have passed since discovering L-DOPA, it is still the best agent for treatment of Parkinson's disease. In the early stages of Parkinson's disease, patients usually enjoy a good response to L-DOPA. As the disease progresses, however, L-DOPA tends to become less helpful. This is not due to the loss of efficacy of L-DOPA, but rather, for example, to development of motor complications such as end-of-dose deterioration or adverse fluctuation in motor response including “wearing-off phenomenon”, “on-off fluctuations”, and dyskinesias.
The “on-off fluctuations” is an event wherein therapeutic benefit of a medication (“on” state, during which the patients are relatively free from the symptoms of Parkinson's disease) is suddenly and unacceptably lost, and the parkinsonian state (“off” state) appears. Such condition occurs when patients with Parkinson's disease are under L-DOPA therapy and exposed to L-DOPA in an amount sufficient to express the efficacy. However, even if such symptoms are expressed, the treatment effect may recover all of a sudden.
The “wearing-off phenomenon” is a phenomenon wherein the duration of L-DOPA action is decreased in patients with Parkinson's disease, even though they are under L-DOPA therapy and exposed to L-DOPA in an amount sufficient to express the efficacy. The phenomenon is characterized by the gradual reappearance of the “off” state, and shortening of the “on” state. That is, it refers to a phenomenon where the duration of the treatment effect of L-DOPA gradually becomes shorter (duration of the treatment effect after administration of L-DOPA becomes shorter), which is remarkably seen in an advanced stage of the disease in patients with Parkinson's disease under L-DOPA therapy.
Dyskinesia can be broadly classified into chorea-like symptoms (hyperactive, purposeless dance-like movement) and dystonia (sustained, abnormal muscle contraction). In 1974, Duvoisin first focused on these abnormal involuntary movements, and found that half or more of patients with Parkinson's disease develop dyskinesia within 6 months of the treatment. With increasing period of treatment, both the frequency and severity of dyskinesia increase. In a study of the potential benefits of possible neuroprotectants in Parkinson's disease-DATATOP trial-, L-DOPA induced dyskinesia was observed in 20-30% of patients who received L-DOPA treatment for a mean of 20.5 months. Ultimately, most L-DOPA treated patients experienced dyskinesia; up to 80% of the patients developed dyskinesia within 5 years. (Annals of Neurology (Ann. Neurol.), vol. 39, p. 37 (1966); The New England Journal of Medicine (N. Eng. J. Med.), vol. 342, p. 1484 (2000)). Most dyskinesias occur when L-DOPA or other dopamine receptor agonists have a concentration in the brain that is sufficient to hypersensitive dopamine receptors in the putamen (peak dose dyskinesia). However, dyskinesia also occurs when the dopamine concentration is low (off-dystonia), or in a stage wherein the concentration of dopamine rises or falls (biphasic dyskinesia).
On the other hand, it is known that adenosine is widely distributed in the whole body, and exhibits a variety of physiological actions on the central nervous system, the cardiac muscle, the kidneys, the smooth muscle, and the like through its receptors (see non-patent document 1), and that an antagonist thereof is useful for the treatment and/or prophylaxis of various diseases.
For example, adenosine A1 antagonists are known to facilitate defecation (The Japanese Journal of Pharmacology (Jpn. J. Pharmacol.), Vol. 68, p. 119 (1995)). Further, the adenosine A2A receptors are known to be involved particularly in the central nervous system, and the antagonists of the adenosine A2A receptors are known to be useful as, for example, therapeutic drugs for Parkinson's disease etc. (see non-patent document 2), therapeutic drugs for sleep disturbance (see Nature Neuroscience, p. 858 (2005); patent document 1) and the like. There are many reports concerning the relationship between adenosine receptors and Parkinson's disease (see, for example, non-patent documents 3 and 4).
In addition, (i) a method of reducing or suppressing side effects of L-DOPA therapy, (ii) a treatment method by reducing the dose of L-DOPA in L-DOPA therapy, (iii) a method of prolonging the duration of effectiveness of the treatment of Parkinson's disease in L-DOPA therapy, (iv) a method of treating a movement disorder and the like, each using an adenosine A2A receptor antagonist, are known (see patent document 2). To be specific, it is known that movement disorders such as tremor, bradykinesia, gait disturbance, akinesia and the like can be suppressed by administering an adenosine A2A receptor antagonist represented by the formula (A) and L-DOPA to patients with Parkinson's disease, and adenosine A2A receptor antagonist represented by the formula (A) suppresses dyskinesia developed by administration of L-DOPA, and the like. Furthermore, it is known that an adenosine A2A receptor antagonist represented by the formula (A) shows an antiparkinson effect in MPTP-treated common marmoset (see non-patent document 5), does not provoke dyskinesia (see non-patent document 6), and does not provoke dyskinesia but potentiates an antiparkinson effect when used in combination with L-DOPA and/or a dopamine agonist (see non-patent document 7).

On the other hand, for example, compounds represented by the formulas (IA), (IB), (IC), (ID) and the like are known to have affinity to adenosine A2A receptors and have a therapeutic effect for Parkinson's disease (see patent document 3). Moreover, thiazole derivatives having an adenosine A2A receptor antagonistic activity are known (see patent document 4). It is also known that these compounds are useful as an agent for the treatment and/or prophylaxis of sleep disturbance (see patent document 1), an agent for the treatment and/or prophylaxis of migraine (see patent document 5), an analgesic tolerance inhibitor (see patent document 6) and the like.
